The mammalian immune system encounters an enormous diversity of foreign agonists, including viruses, bacteria, protozoa, parasitic worms (helminths), and allergenic particles. Determining how the immune system first senses and distinguishes these agonists is fundamental to our understanding of the immune response and accordingly to our therapeutic interventions. The discovery that Toll-like receptors bind bacterial lipopolysaccharide established a foundational paradigm in immune sensing in which microbial ligands are detected by cognate immune receptors. Many ligand-receptor pairs have since been identified and our understanding of bacterial and viral ?type 1? detection is quite advanced. By contrast, very little is known about how the immune system first senses helminths and allergens, all of which give rise to the same ?type 2? immune response. We recently discovered that during intestinal helminth infection, the type 2 immune response requires an epithelial cell type with previously unknown function: the tuft cell. This finding not only ?de-orphanized? the enigmatic tuft cell lineage but may also provide the missing link between pathogen and host in type 2 immune sensing. Tuft cells directly contact the intestinal lumen where helminths reside, and uniquely among intestinal epithelial cells, they encode a chemosensing pathway that centers on the Ca2+-gated cation channel TRPM5. Type 2 immune responses are defective in Trpm5-deficient mice, implicating a sensing function for tuft cells. In this proposal we aim to understand how intestinal tuft cells sense helminth infection, thereby employing an entirely new and innovative entry point to understanding type 2 immune sensing. First, we combine in vivo and in vitro screening approaches to identify a ligand associated with helminth infection that activates tuft cells and drives type 2 inflammation. Next, we seek to identify a receptor on tuft cells that generates the Ca2+ flux required to open TRPM5 and subsequently control helminth infection. We also seek to develop new techniques for in vitro culture of tuft cells, an advance that would support both our own research and the emerging interest in tuft cells generally. Although focused on helminth infection, if successful this work would establish a novel paradigm for the initiation of type 2 immune responses and should provide insights into the detection of allergens and other type 2 agonists as well. Our findings may therefore uncover novel therapeutic targets for treating both helminth infection and allergic inflammation.